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Rheumatology 2000; 39: 463-470
© 2000 British Society for Rheumatology

Review

Nuclear medicine in vasculitis

Vasculitis/Series Editor: R. Watts

A. M. Peters

Department of Nuclear Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK

Nuclear medicine has several roles to play in the management of patients with systemic vasculitis. They can be subdivided as follows:

(1) in vitro sample counting such as for the determination of glomerular filtration rate (GFR) in patients with suspected renal impairment;
(2) non-specific imaging of ischaemic and inflammatory complications of vasculitis, such as ventilation/perfusion lung scanning in patients with involvement of medium-sized and large pulmonary arteries, and brain perfusion imaging in patients with cerebral vasculitis;
(3) specific imaging of inflammation using radioactive agents that specifically target a component of the inflammatory process, in order to
(a) help occasionally make the diagnosis in a patient presenting with non-specific symptoms and equivocal serology;
(b) define the distribution of inflammatory lesions;
(c) monitor the response of inflammatory lesions to treatment;

(4) the use of radioactive agents to improve our understanding of the pathophysiology of vasculitic diseases.

The measurement of GFR is now almost exclusively undertaken in departments of nuclear medicine. The use of Cr-51-ethylenediamine tetraacetic acid (EDTA) or Tc-99m-diethylenetriamine pentaacetic acid (DTPA), given by bolus intravenous injection followed by measurement of plasma clearance, should have made creatinine clearance virtually obsolete. The sophistication of measurement techniques varies from those based on a single sample of blood taken at a specified time point after injection to multisample techniques, but all are more accurate than creatinine clearance and much more convenient for the patient. The author prefers an approach in which only the rate constant of the terminal exponential is measured (i.e. between 2 and 4 h after injection)—nothing else—as this rate constant is a close approximation to the quotient GFR to extracellular fluid volume and is therefore an expression of GFR that is already normalized for the size of the patient [1]. Indexation of GFR to body surface area is more labour intensive and has the disadvantage of spuriously reducing apparent renal function the smaller the individual (since small objects have a higher surface area to weight ratio compared with identically shaped larger objects).

The complications of systemic vasculitis are protean, arising from cerebral ischaemia, pulmonary arteritis, skin and soft tissue ulceration, mesenteric ischaemia, renal impairment which may be asymmetrical, and so on, and most of these can be monitored by scintigraphic imaging. Takayasu's arteritis, for instance, may give a picture on V/Q scanning identical to that seen in pulmonary embolic disease, emphasizing the non-specificity of nuclear medicine imaging. Moreover, the appearances of gut vasculitis on leucocyte scanning may be no different to those of inflammatory bowel disease.

The most important role of nuclear medicine in systemic vasculitis is the use of inflammation-specific agents to monitor the inflammatory activity of the disease. Numerous agents have now been described for targeting inflammation, so much so that it is now useful to classify them [2]. The classification in Table 1Go is based on the cell or receptor targeted by the radiochemical and the relationship of that target to the endothelium. For example, although they target the inflammatory process at several levels, labelled leucocytes, whether labelled in vitro [3, 4] or with a specific monoclonal antibody in vivo [5], can be classified as pre-endothelial since they are already labelled before arrival at the inflammatory lesion.


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  		TABLE 1. Radiochemicals for imaging inflammation

 
An interesting approach to imaging inflammation is to target endothelial adhesion molecules that are expressed during inflammation [6–8]. Endothelium is metabolically very active and orchestrates leucocyte migration through the activation of a cascade of adhesion molecules, which govern leucocyte margination, adherence, spreading and eventually transendothelial migration. Adhesion molecules attractive for imaging inflammation are those that are only expressed during inflammation (i.e. are not constitutively expressed), are present only on endothelium, are expressed on the luminal side of the endothelial cell, not shed into the circulation, and internalized along with the monoclonal antibody following binding. E-selectin, a member of the selectin family, fulfils these specifications rather well. It is synthesized de novo over a period of about 45 min by the endothelial cell in response to several cytokines. After antibody binding to E-selectin, the immune complex is internalized, with only minimal shedding into the circulation, in contrast to vascular cell adhesion molecule-1 (VCAM-1), for instance, which is largely shed when it binds specific antibody [9]. Haskard et al. have characterized E-selectin expression in several models of experimental inflammation [7, 8] and in clinical inflammation (Fig. 1Go) [10–12], showing in particular that expression is closely linked to lymphocyte migration as well as neutrophil migration [8]. This is a tantalizing finding in view of the dearth of effective agents for imaging chronic inflammation.



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  		FIG. 1. Gamma camera images of active rheumatoid arthritis of the knees acquired with In-111-HIG (left) and In-111-anti- E-selectin (right) in the same patient 1 week apart. Note the more intense and focalized (to the synovium) activity seen with anti-E-selectin. (Reproduced from Arthritis and Rheumatism).

 
Several macromolecules are in use or development which, in general, access the inflammatory lesion by diffusing through the endothelium as a result of increased microvascular permeability and so can be classified as endothelial. As a result of increased vascularity, increased endothelial permeability and a locally expanded interstitial fluid space, radiolabelled macromolecules accumulate non-specifically in inflammation and may be used to image it (Fig. 1Go). Ga-67, which is a commonly used agent for imaging inflammation, is taken up predominantly by this mechanism as a metal–transferrin complex, followed by local binding to transferrin receptors [13]. Polyclonal immunoglobulin (HIG) has been introduced more recently for imaging inflammation, and, in spite of early claims for several active mechanisms of localization, is now known to accumulate passively as a result of increased endothelial permeability [14]. Although Tc-99m-HIG is commercially available, the evidence suggests that In-111-HIG is better, especially in more chronic inflammation/infection. This is because the In-111 firmly transchelates from HIG to extravascular local proteins, leaving the HIG to diffuse back into plasma [14]. Tc-99m, on the other hand, remains bound to the HIG and diffuses back into plasma with it, or, alternatively, re-enters plasma as the free metal because it is less firmly bound to protein than In-111. A general principle of nuclear medicine imaging, illustrated here, is that positive images ultimately reflect the distribution of the radiolabel rather than the pharmaceutical to which it is attached.

Radiolabelled liposomes, which are spherical envelopes of cell membrane of about 100 nm diameter, have been explored for imaging inflammation by several groups over many years. Early efforts met with no success largely because circulating liposomes are taken up very quickly by the reticuloendothelial system (RES) with a halftime in blood which is so short that not enough time is available to localize elsewhere. Interest has recently been rejuvenated, however, by the development of so-called ‘stealth’ liposomes. These have an outer coating of polyethylene glycol (‘pegylated liposomes’) which results in a failure to be recognized by phagocytes, and which results in a much longer clearance time from blood, measurable in hours. They can be labelled internally with either Tc-99m-hexamethylpropyleneamine oxime (HMPAO) or In-111-oxine, utilizing the same principles as cell labelling. Recent work by Corstens et al. [15, 16] has shown that stealth liposomes may be as effective as In-111-HIG or labelled leucocytes for localizing inflammation. Other attractions of liposomes are (a) the possibility of directing them to specific targets by attaching molecules, such as monoclonal antibodies, to their surface [17], and (b) placing materials inside them such as drugs or, for imaging purposes, paramagnetic or radioactive materials [17].

Other agents have targets which are on the interstitial side of the endothelium and can therefore be classified as post-endothelial. These include radiolabelled antibiotics [18], fluorine-18-fluorodeoxyglucose (FDG), which is taken up by metabolically active inflammatory cells [19–26], and cytokines which target leucocyte receptors activated following migration [27].

FDG is an analogue of glucose for which an increasing value in cancer imaging using positron emission tomography (PET) is becoming appreciated. Following cellular uptake, it is metabolically trapped and consequently gives an image which portrays tissue glucose utilization. It is highly effective for imaging tumours because malignant cells in general display marked up-regulation of glucose transfer enzymes, including hexokinase. In contrast to the largely inappropriate increased uptake of glucose of cancer, inflammatory cells take up large amounts of glucose as a result of an increased metabolic rate (Fig. 2Go). Indeed, inflammatory foci are the main causes of false positive FDG scans performed for malignant disease. FDG therefore represents a promising agent for localizing inflammation and reports are beginning to appear in the literature on the use of dedicated PET and FDG for this application. Thus, there is a substantial series in chronic osteomyelitis [19], some short reports in synovitis [20] and temporal arteritis [21] and several abstracts on infected joint prostheses [22]. A recently completed study has shown that inflammatory bowel disease also gives strongly positive images [23]. However, in none of these studies were comparisons made with labelled leucocytes so the contribution of granulocyte migration to the images remains unclear. This is important because the mononuclear cells of chronic inflammation are also metabolically active. Thus, FDG accumulates in granulomatous lesions and there are recent reports of successful FDG imaging in sarcoidosis [24] and tuberculosis [25]. Moreover, atherosclerosis has been shown to be positive on FDG–PET, assumed to be the result of macrophage infiltration of the arterial wall [26].



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  		FIG. 2. Whole body coronal (left) and transaxial (right) tomographic images in a patient with active tuberculosis of both upper zones of the lungs acquired 1 h following injection of [F-18]FDG using a rotating dedicated positron scanner (ECAT ART). Normal urinary activity is also visible.

 
Leucocytes radiolabelled in vitro remain the most widely used marker of inflammation, including vasculitis [28, 29]. It is important to appreciate that because of cell numbers in blood and the intrinsic sensitivity of lymphocytes to ionizing radiation, which prevents them from recirculating normally through the lymphoid system within hours of labelling [30], the effective ingredient in a labelled leucocyte preparation is the neutrophil. Indeed, the imaging qualities of this technique are improved by the use of labelled purified neutrophils. Thus, only pyogenic inflammation is effectively visualized by labelled leucocytes and this limits their scope in diseases such as vasculitis where the chronicity of inflammation and its neutrophilic content may vary widely. The applications of labelled leucocytes in vasculitis are
  • • occasionally to point to the diagnosis;
  • • to define the distribution of disease;
  • • for monitoring the inflammatory activity of the disease;
  • • to improve our understanding of the pathophysiology of the disease, especially with respect to neutrophil trafficking through several organs.

Patients with vasculitis may present as undiagnosed fever and undergo leucocyte scanning as part of their diagnostic workup. Leucocytes can be labelled with either Tc-99m (t1/2 6 h) or In-111 (2.7 days) using lipid-soluble chelates {HMPAO for Tc-99m [4] and tropolone or hydroxyquinoline (oxine) for In-111 [3]} which transport the radionuclide across the cell membrane. The normal distribution of Tc-99m leucocytes is the RES, which reflects the biodistribution of leucocytes, but in, addition, several other areas of uptake in normals are seen which reflect the relatively poor stability of Tc-99m within cells and the subsequent distribution of soluble derivatives of Tc-99m-HMPAO [4]. These include the urinary tract, gall bladder and gut. The normal distribution of In-111 leucocytes is confined to the RES because In-111, as a heavy metal, is not permitted access to body fluids unless transported there ‘on board’ neutrophils (Fig. 3Go). Any activity outside the RES (apart from early blood pool activity) is therefore abnormal. After release into the blood from bone marrow, neutrophils circulate with a t1/2 of about 7 h [31]. Because of highly stable labelling, In-111 neutrophils retain a 7 h half-life but, for Tc-99m neutrophils, the t1/2 is only about 4 h. This does not reflect cellular damage but is the result of elution of the Tc-99m label, which is less firmly bound [32].



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  		FIG. 3. Active Crohn's disease, involving predominantly the distal ileum, imaged with In-111-labelled neutrophils. The image (anterior abdomen) acquired 3 h following injection illustrates the distribution of active inflammation; the image acquired 20 h later shows labelled neutrophils throughout the colon, which is not inflamed, as a result of migration into bowel lumen, at sites of active disease, followed by distal transit with luminal contents. Quantification of all the radioactivity in faeces, collected over 4 days from injection, gives an accurate and reproducible measure of the extent and inflammatory activity of the disease.

 
Although Tc-99m leucocytes give images of better resolution than In-111 leucocytes, the latter are preferred for imaging inflammation in vasculitis because of the varied distribution of the abnormalities, and because the cellular basis for them is unpredictable. Typical features of vasculitis, which may suggest the diagnosis, include marked early pulmonary activity (Fig. 4Go) (which clears in parallel with the clearance of labelled neutrophils from the blood), reflecting prolonged neutrophil transit through the pulmonary vasculature (see below), focal areas of increased soft tissue neutrophil uptake and, in the case of Wegener's granulomatosis, intense uptake in the nasal region (Fig. 5Go). Focal areas of increased uptake, in addition to the nasal region, may be due to meningeal involvement and soft tissue granulomata almost anywhere. The spleen is normally a site of intense activity which is the result of physiological neutrophil pooling, so splenic granulomata are more likely to be seen as photopaenic areas. Focal pulmonary abnormalities, and evidence of nephritis and gut vasculitis may be seen. It is impossible to diagnose nephritis with Tc-99m-labelled leucocytes because of normal renal uptake of complexes resulting from degraded HMPAO. Renal activity following injection of In-111 leucocytes, whether diffusely distributed throughout the parenchyma or within the collecting system, is unequivocally abnormal. Cerebral vasculitis, on the other hand, is best imaged with Tc-99m leucocytes because of the advantage of improved resolution, and single photon computerized emission tomography (SPECT) can be attempted.



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  		FIG. 4. Increased activity diffusely in the lungs of a patient with Wegener's granulomatosis 3 h following injection of In-111-labelled leucocytes. Whole body images (anterior: left; posterior: right) show no evidence of active inflammation. The spleen, which is normally prominent as a result of physiological leucocyte pooling, is markedly reduced in size as a result of granulomatous replacement.

 


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  		FIG. 5. Whole body images (anterior: left; posterior: right) in a patient with Wegener's granulomatosis 24 h following injection of In-111-labelled leucocytes. There are multiple sites of active inflammation which are recruiting the labelled cells, including nose, lungs (bilaterally), abdomen and pelvis.

 
The changes that may be anticipated in an image based on an inflammation-specific agent following successful treatment in a patient with vasculitis depend on which component of the inflammatory process the agent portrays. For example, immunotherapy with anti-CD18 would be expected to attenuate neutrophil migration but to have less effect on E-selectin expression. The least specific agents may therefore be the most useful for monitoring the effects of treatment and these would include the macromolecules which simply mark increased vascular permeability and FDG which marks inflammatory cell activity. Because of the better image resolution of PET, either with a dedicated positron camera or gamma camera with coincidence circuitry, FDG–PET is an exciting potentially very useful technique for monitoring a range of inflammatory conditions, including vasculitis. This illustrates a general rule in clinical nuclear imaging which is that radiochemicals with low specificity have, by and large, wider general use than specific agents. In contrast, for testing new therapeutic approaches, for instance a putative new drug with the possible effect of down-regulating or blocking E-selectin expression, a specific agent would be preferable.

It has emerged recently that systemic vasculitis is associated with several abnormalities of neutrophil physiology and traffic, the most prominent of which is increased diffuse pulmonary activity on early images [33]. This lung activity tends to clear over a few hours, in parallel with the physiological clearance of labelled neutrophils from the circulation, and is the result of delayed transit of neutrophils through the pulmonary microcirculation. In normal individuals, neutrophils transit the lung capillaries more slowly than red cells, taking longer by a factor that has variously been estimated to be between 15 and 60 [33–35]. This is because neutrophils have a diameter larger than that of pulmonary capillaries and must, therefore, deform to reach pulmonary venules. Direct observations through chest wall windows in dogs have shown how neutrophils arriving from pulmonary arterioles may suddenly be arrested in capillaries for variable periods of time before escaping, either to pass directly to a venule or to become arrested again downstream in the same capillary bed [34].

If neutrophils become stiffer than normal for any reason they take longer to transit the pulmonary vascular bed. A cause of reduced deformability is neutrophil priming [36, 37] and this is almost certainly the basis for the increased lung activity seen in vasculitis. Ussov et al. [33] measured mean pulmonary intravascular time in a range of systemic inflammatory conditions, including systemic vasculitis, inflammatory bowel disease and graft vs host disease (Fig. 6Go), and showed that it significantly correlated with the level of neutrophil priming—measured using a simple microscopic shape change assay—in peripheral venous blood. The lungs of these patients showed no clinical evidence of damage, although subclinical damage could be detected from the alveolar clearance rate of inhaled Tc-99m-DTPA aerosol. There was no correlation between clearance rate and pulmonary vascular transit time, implying that the lung is not injured as long as neutrophils remain in the vascular space and only becomes damaged if neutrophils migrate through the pulmonary capillary endothelium into the extravascular space. The residual In-111 signal at 24 h, taken to represent the level of neutrophil migration into the extravascular space where the label would be trapped after migration, did correlate with Tc-99m-DTPA clearance rate, an observation consistent with the hypothesis that lung is at risk of injury following transendothelial neutrophil migration.



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  		FIG. 6. Tc-99m-HMPAO leucocyte images in a patient with graft vs host disease, showing intense reversible diffuse retention of cells in the lungs (right) and multiple segments of inflamed small bowel (left).

 
In conclusion, nuclear medicine techniques have a wide and varied role in patients with vasculitis, contributing to clinical management, pathophysiological studies of leucocyte kinetics, and evaluation of new therapies, particularly immunotherapy. Studies of leucocyte kinetics in vasculitis have helped us to understand the normal physiology of leucocyte traffic, and conversely advances in radionuclide imaging have helped us to understand and manage vasculitis.


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Submitted 8 November 1999; Accepted 20 December 1999


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